The digestive distress that commonly accompanies Autism Spectrum Disorders (ASDs) significantly degrades the quality of life of those affected and their families. ASDs are currently estimated to impact 1 in 88 children, and yet the co-occurring gastrointestinal (GI) distress is understudied, having only recently been recognized by the medical establishment; in fact, there are currently no unified treatment strategies for ASD-linked GI distress. Our goal is to identify the mechanisms that underlie GI distress in ASD as a means to suggest effective therapeutic strategies. To do this, we have developed zebrafish models of one of the most prevalent genetic forms of ASD, Phelan McDermid Syndrome. This syndrome's GI symptoms include diarrhea, reflux, and cyclical vomiting. Phelan McDermid Syndrome is known to be caused by loss of one copy of the SHANK3 gene, a condition our team has been able to replicate in zebrafish. Our zebrafish model provides an innovative way to determine the mechanisms by which shank3 mutations are related to the symptoms of GI distress. Zebrafish have two unique characteristics that make them an ideal model for this work: their larvae are transparent, allowing us to see their GI function in process, while they are still alive; and we can study the development of regulatory circuits to identify those shank3 mutant tissues that produce GI distress. In addition, zebrafish and human nervous systems and GI tracts are remarkably similar, suggesting that the mechanisms we discover will be applicable to both. The zebrafish's small size and aquatic habitat also support targeted pharmacological screens to test therapeutic strategies. In aim one, we test how the shank3 mutations that cause Phelan McDermid Syndrome affect the development of tissues known to regulate GI function. In aim two, we test whether hormones and neurotransmitters known to regulate GI function can improve digestion in the shank3 mutant fish. There is a tremendous need to address GI distress in ASD. This project will improve our understanding of this problem and will pave the way for developing solutions.